EP0996612B1 - Propargylamines aliphatiques employes comme antidotes electifs - Google Patents

Propargylamines aliphatiques employes comme antidotes electifs Download PDF

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EP0996612B1
EP0996612B1 EP98933408A EP98933408A EP0996612B1 EP 0996612 B1 EP0996612 B1 EP 0996612B1 EP 98933408 A EP98933408 A EP 98933408A EP 98933408 A EP98933408 A EP 98933408A EP 0996612 B1 EP0996612 B1 EP 0996612B1
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propargylamine
compound
formula
heptyl
octyl
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EP0996612A2 (fr
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I. Alick Paterson
David A. Durden
Bruce A. Davis
Lillian E. Dyck
Peter H. Yu
Xin-Min Li
Alan A. Boulton
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University of Saskatchewan
Saskatchewan University of Technologies Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/20—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
    • C07C211/23—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton the carbon skeleton containing carbon-to-carbon triple bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to a class of propargylamines, their salts and to pharmaceutical compositions containing such compounds.
  • the compounds have cellular rescue properties which make them useful in the treatment and prevention of diseases in which cell death occurs by apoptosis.
  • Neurodegenerative disorders of both acute types e.g. stroke, head trauma, Bell's palsy, spinal cord and other nerve crush injuries
  • chronic types e.g. Alzheimer's disease, Parkinson's disease, Picks's disease, amyotrophic lateral sclerosis, Huntington's disease, glaucoma, as well as idiopathic neuropathies
  • Alzheimer's disease, Parkinson's disease, Picks's disease, amyotrophic lateral sclerosis, Huntington's disease, glaucoma, as well as idiopathic neuropathies are responsible for enormous human suffering, are a burden on health care systems and result in significant economic loss.
  • a drug or treatment which could prevent, delay or alleviate one or more of these conditions would be of immense value.
  • R-Deprenyl hydrochloride (selegiline, L-deprenyl) has been demonstrated to be an effective adjuvant to L-dopa in the treatment of Parkinson's disease and, in early otherwise untreated cases, it has more recently been reported to delay onset of symptoms when administered alone. It has also been claimed that the use of deprenyl improved the clinical condition of some Alzheimer patients and the symptoms of attention deficit disorder in Tourette's syndrome patients. In addition, it has been observed to prolong life span and sexual activity in rodents and humans.
  • deprenyl can prevent apoptosis by a mechanism which involves selective alterations in gene expression to block the loss of mitochondrial function which in turn would commit these cells to apoptosis.
  • Deprenyl has also been shown to prevent N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)-induced degeneration of rat brain noradrenergic axons and terminals.
  • DSP-4 N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine
  • the concentrations of deprenyl required to prevent apoptosis are at least an order of magnitude lower than the minimum necessary for MAO-B inhibition in some of these models. Furthermore, not all MAO-B inhibitors are effective in rescuing damaged neurons.
  • Deprenyl is metabolized to amphetamine and methamphetamine which have been observed to be neurotoxic even at quite low concentrations, which creates a possible problem with deprenyl as a neuronal rescue drug. Similarly deprenyl has been shown to enhance the cytotoxicity of dopamine towards catecholaminergic neuroblastoma SH-SY5Y cells. Deprenyl has been demonstrated to be a substrate for cytochrome P450 enzymes, which mediate the dealkylation process leading to the observed metabolites, methamphetamine and desmethyldeprenyl.
  • Desmethyldeprenyl is active as an anti-apoptotic drug and studies involving the inhibition of P450 enzymes have shown that desmethyldeprenyl is the active component when deprenyl is given since pretreatment with a P450 inhibitor such as proadifen eliminates the neurorescue properties of deprenyl. It has also been reported that the desmethyldeprenyl-like compound, N-propargyl-1-aminoindan, is effective in enhancing the in vitro neuronal survival after glutamate toxicity.
  • French Patent No. 1 453 844 discloses propargylamines of the following general formula R-CH 2 -CH(CH 3 ) -N(R')-CH 2 -C ⁇ CH wherein R represents a linear or branched alkyl radical containing 3 to 6 carbon atoms and R' represents a hydrogen atom or a methyl group as well as the acid addition salts. This document also describes certain pharmacological properties of these compounds in terms of the activity as mono-amine oxidase inhibitors.
  • Ben-Efraim (Tetrahedron, Vol. 29, pp. 4111-4125 (1973)) discloses a number of propargylic amines including N-(1-heptyl)propargylamine without reference to any pharmacological properties of these compounds.
  • deprenyl has proven to be as effective MAO-B inhibitors as deprenyl (U.S. Patent Nos. 5,169,868 and 5,508,311). As with deprenyl, it is the R-enantiomers which are active. They have also been shown to protect and rescue damaged neurons in the same models of neurodegeneration described above for deprenyl.
  • the aliphatic desmethyl propargylamines identified in this application are active as antiapoptotic compounds.
  • the present invention provides a propargylamine of the general formula I wherein R 1 is hydrogen or CH 3 and R 2 is (CH 2 ) n CH 3 and n is an integer from 0 to 16, preferably 1 to 10, more preferably 1 to 5, with the provisos that:
  • the present invention also provides a commercial package containing as active ingredient a compound of formula I, or a pharmaceutically acceptable salt thereof, together with instructions for its use in the treatment of a disease in which cell death occurs by apoptosis.
  • the present invention relates to (the use of) a propargylamine of general formula I, wherein R 1 is hydrogen or CH 3 and R 2 is (CH 2 ) n CH 3 where n is an integer from 0 to 16, and salts thereof.
  • R 1 differs from R 2
  • R 2 Compounds of the general formula I in which R 1 differs from R 2 are chiral. It has been found that the R-enantiomers are useful as cellular rescue agents for the treatment and prevention of diseases in which cell death occurs by apoptosis. This effect is observed at doses much lower than those required for MAO-B inhibition.
  • the S-enantiomers do not prevent apoptosis but can antagonise the anti-apoptotic actions of the R-enantiomers, and are useful as research tools.
  • the achiral compounds display cellular rescue properties.
  • racemates are useful as intermediates in the preparation of R- and S-enantiomers.
  • Methods of separating racemates are known. Suitable methods include fractional crystallization of a suitable salt, chromatography and preparation of for example N-acetyl derivatives, followed by deacetylation of one enantiomer with a stereospecific enzyme. It is preferred, however, to make chiral compounds of formula I from chiral reactants, using reactions that do not destroy the stereochemistry.
  • an enantiomer shall not contain more than about 3% of the enantiomer of the opposite configuration. It is particularly preferred that an enantiomer contain less than about 1% of the enantiomer of the opposite configuration.
  • Preferred compounds of the invention or used according to the invention include:
  • the S-enantiomers antagonize the effect of the R-enantiomers, and are useful as research tools.
  • Preferred compounds of the S-configuration are:
  • Particularly preferred as cellular rescue agents are those compounds of the R configuration.
  • the S-enantiomers antagonize the antiapoptotic actions of the R-enantiomers, and are useful as research tools.
  • the invention extends to salts of compounds of formula I.
  • the salts should be pharmaceutically acceptable, but other salts may be useful, for example, in synthesis or for purification.
  • amine of the formula II in which R 1 differs from R 2 in the form of a racemate and to separate enantiomers subsequently, but it is preferred to use an amine in substantially enantiomerically pure form.
  • two equivalents of amine are reacted with one equivalent of the compound of formula III, preferably propargyl bromide to form the required propargylamine and the hydrobromide salt of the amine, which can be isolated and reused, in accordance with the following reaction scheme.
  • Another route to compounds of the invention involves ( b ) reacting a compound of the formula IV wherein R 1 and R 2 are as defined above, with alcoholic hydroxide, to remove the trifluoroacetyl group.
  • the compound of formula IV can be obtained by a process that involves trifluoroacetylation of the amine, followed by propargylation.
  • the amine can be used in racemic or enantiomerically pure form.
  • the amine is reacted with trifluoroacetic anhydride or a trifluoroacetyl halide in an inert organic solvent, for instance a chlorinated hydrocarbon such as methylene dichloride, chloroform or carbon tetrachloride, and a base, for example an organic base such as triethylamine.
  • N-trifluoroacetylamine is then refluxed with a propargyl compound of formula III, suitably in the presence of a base such as potassium t-butoxide in a polar organic solvent, for example acetonitrile, and in the presence of a crown ether, for example 18-crown-6.
  • a base such as potassium t-butoxide in a polar organic solvent, for example acetonitrile
  • a crown ether for example 18-crown-6.
  • the product of this reaction is then hydrolysed, suitably by reaction with a base such as an alkali metal hydroxide in an alcoholic solution.
  • a preferred embodiment is shown in the following reaction scheme. Trifluoroacetylation of Amine then Propargylation: wherein R 1 and R 2 are as defined above.
  • Compounds of formula I can also be prepared by (c) reacting a compound of formula V wherein R 1 and R 2 are as defined above and R is lower alkyl preferably (C1-C2) alkyl, with an acid.
  • the compound of formula V can be obtained by phosphorylating and then propargylating an amine.
  • the amine can be a racemate but is preferably a substantially pure enantiomer.
  • An amine of formula II is reacted with a dialkylphosphite, for example diethyl or dimethyl phosphite, preferably in an organic solvent such as carbon tetrachloride, in the presence of an aqueous hydroxide, such as NaOH, and in the presence of a phase transfer catalyst such as benzyltriethylammonium chloride or tetrabutyl ammonium hydrogen sulfate.
  • the phosphorylated amine is then reacted with a propargyl compound of formula III, preferably in the presence of aqueous base, such as NaOH, in the presence of a phase transfer catalyst, such as tetrabutyl ammonium hydrogen sulfate or benzyltriethylammonium chloride.
  • a phase transfer catalyst such as tetrabutyl ammonium hydrogen sulfate or benzyltriethylammonium chloride.
  • the compounds of the invention are useful in the prevention and treatment of diseases in which cell death occurs by apoptosis.
  • the present invention provides a use of a compound of the formula I that is achiral or is a substantially pure R-enantiomer, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of a condition in which cell death occurs by apoptosis.
  • Preferred compounds of the formula I that may be used for the preparation of a medicament for the treatment or prevention of a condition wherein cell death occurs by apoptosis include:
  • the compound of the formula I is chiral and is a substantially pure R-enantiomer.
  • substantially pure R-enantiomer means that the compound does not contain more than 3%, and preferably less than 1%, of the S-enantiomer.
  • the compound is R-2HPA.
  • Conditions wherein cell death occurs by apoptosis include, but are not limited to, stroke, head trauma, Bell's palsy, spinal cord and other nerve crush injuries, Alzheimer's disease, Parkinson's disease, Pick's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, cardiac myopathies, nephropathy, retinopathy, diabetic complications, glaucoma, idiopathic neuropathies as well as any condition wherein there is a degeneration of cells.
  • the compounds of the invention may also be used prophylactically to prevent premature degeneration of cells.
  • effective amount means an amount effective, at dosages and for periods of time necessary to achieve the desired result.
  • animal as used herein includes all members of the animal kingdom, preferably humans.
  • the present invention further includes a commercial package containing as active ingredient a compound of formula I that is achiral or is a substantially pure R-enantiomer, or a pharmaceutically acceptable salt thereof, together with instructions for its use for the treatment or prevention of a condition in which cell death occurs by apoptosis.
  • the compounds of the general formula I may be formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo.
  • the compositions containing the compounds of the invention can be prepared by per se known methods for the preparation of pharmaceutically acceptable compositions which can be administered to subjects, such that an effective quantity of the active substance is combined in a mixture with a pharmaceutically acceptable vehicle.
  • Suitable vehicles are described, for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA 1985).
  • the compositions include, albeit not exclusively, solutions of the substances in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids.
  • the active substance may be administered in a convenient manner such as by injection (subcutaneous, intravenous, etc.), oral administration, inhalation, transdermal application, or rectal administration.
  • the compounds may be administered as tablets, coated tablets, gelatine capsules, capsules, cachets, and solutions or suspensions to be taken orally.
  • the compounds can also be administered parenterally or through any other suitable administrative route such as intravenous, subcutaneous, depot injections, intramuscular, intrathecal, intraventricular, intra-articular, rectal (suppository, enema), sublingual, buccal, intra-ocular, intra-vitreo, transdermal (skin patch), nasal drops (nebulizer, infufflation), liposomal delivery systems.
  • the daily dosage could likely range from 1 to 100 mg.
  • CGC cerebellar granule cells
  • R-2HPA had an EC50 of about 10 -11 M ( Figure 1A).
  • (R)-N-(2-heptyl)-N-methyl-propargylamine(R-2HMP) had an EC50 between 10 -9 and 10 -7 M ( Figure 1B).
  • Figure 1C the stereospecific effect of the R-isomers using aliphatic methyl propargylamines (R-2HMP and S-2HMP) and deprenyls (R-deprenyl and S-deprenyl) ( Figure 1C).
  • Apoptosis of hippocampal pyramidal neurons can be induced in vivo using a rat model of hypoxia/ischaemia (Paterson et al., 1997). This model produces selective, unilateral lesioning of the pyramidal neurons in the hippocampus which involves neuronal apoptosis.
  • R-2HPA was found to be capable of preventing kainic acid-induced neuronal damage.
  • Heat shock protein-70(HSP70) and delayed c-Fos expressions have been found to be markers for neuronal injury following kainic acid-induced seizures (Zhang et al, 1996).
  • the levels of both proteins were measured 24h after a single injection of kainate (10 mg/Kg,i.p).
  • the levels can be seen in Table 5.
  • R-2HPA was able to block the expression of both genes in the rat hippocampal CA1 region. This suggests that this compound can rescue these neurons.
  • the inhibition of the rat liver mitochondrial monoamine A and B activity by R- and S-enantiomers of the compounds of the invention and of the previously reported aliphatic N-methylpropargylamines, (i.e. the corresponding N-methyl analogues) is shown in Table 6.
  • N-(2-butyl)-propargylamine (2BuPA), N-(2-hexyl)-propargylamines (2HxPA) and N-(2-heptyl)-propargylamine (2HPA), are substantially reduced in comparison to those of the N-methyl compounds, N-(2-butyl)-N-methyl-propargylamine (2BuMP), N-(2-hexyl)-N-methyl-propargylamine (2HxMP) and N-(2-heptyl)-N-methyl-propargylamine (2HMP).
  • the R-enantiomers of the aliphatic propargylamines are more active than the S-enantiomers.
  • R-2HPA exhibits a weaker inhibitory effect on the mouse brain MAO-B with the ED 50 value 20 fold higher than that of its parent compound R-2HMP, which is 2.5 fold more potent than R-deprenyl. None of the compounds inhibit MAO-A in vivo or in vitro.
  • R-Deprenyl has been proposed to possess neuroprotective effects and one of the proposed mechanisms is that R-deprenyl induces superoxidase dismutase (SOD) activity, which would result in the inactivation of singlet oxygen.
  • SOD superoxidase dismutase
  • the induction of free radicals with the succeeding cascade reactions of lipid peroxidation are known to cause neuronal damage. Regulation of SOD activity is involved in several different pathological situations, such as brain ischemia, aging, and neurodegenerative diseases.
  • PC12 cells were used to study the gene regulation of SOD (copper, zinc-dependent type, i.e. SOD1) by (R)-2-heptylpropargylamine (R-2HPA).
  • SOD1 copper, zinc-dependent type, i.e. SOD1
  • R-2HPA -2-heptylpropargylamine
  • LNGFR also called the p75 NGF receptor
  • p75 is a 75 kDa transmembrane protein with an incompletely characterized function.
  • p75 has some sequence similarity to the tumor necrosis factor receptors, Fas antigen, CD40 and Apo-1, all of which mediate cell death.
  • p75 expression induces neural cell death constitutively when LNGFR is unbound.
  • Mutant PC12 cells (LNGFR deficiency clone) better survive apoptosis induced by NGF or serum withdrawal than the wild type PC12 cells. Binding by NGF or monoclonal antibody, however, inhibits cell death induced by LNGFR.
  • NGF monoclonal antibody
  • the higher level of LNGFR expression in the central nervous system occurs in the cholinergic neurons of the nucleus basalis of Meynert, the cells most severely affected in Alzheimer's disease. These cells continue to express normal or supranormal amounts of LNGFR mRNA and protein during the neuronal degeneration associated with Alzheimer's disease. In contrast, cholinergic cells of the brainstem that resemble those of the nucleus basalis morphologically do not express LNGFR, nor do they degenerate in Alzheimer's disease.
  • N-2-Propylpropargylamine hydrochloride [N-2-propynyl-2-propanamine] 2PrPA (This compound is not claimed per se.)
  • N-1-Pentylpropargylamine hydrochloride [N-2-propynyl-1-pentanamine] 1PePA (This compound is not claimed per se.)
  • N-1-Hexylpropargylamine hydrochloride [N-2-propynyl-1-hexanamine] 1HxPA (This compound is not claimed per se.)
  • ⁇ -Phenylethylamine was used as the MAO-B substrate. Enzyme activity was assessed using a radiometric method as previously described (Yu et al, 1992). Effect of R-2HMP, R-2HPA and R-deprenyl on mouse brain MAO-B activities after intraperitoneal administration of the drugs Inhibitors* ID 50 (mg/Kg) PE Comparison (1.9x10 -5 M) to most effective inhibitor R-2HMP 0.2 100% R-2HPA 4 5% R-deprenyl 0.5 40% Results are the average of two independent triplicate experiments for each i.p. dose. The doses were 0.5, 1, 2, 5, 10, 20 mg/Kg. Striata were dissected from the brain two hours after i.p. administration of the drugs.
  • Cytosine arabinoside induces apoptosis in cerebellar neurons in culture. J. Neurochem., 64, 1980-1987.
  • Aliphatic propargylamines potent, selective, irreversible monoamine oxidase B inhibitors. J. Med. Chem., 35,3705-3713.

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Claims (24)

  1. Composé de formule I:
    Figure 00600001
    dans laquelle
       R1 représente H ou CH3,
       R2 représente CH3(CH2)n,
       et n représente un nombre entier valant de 0 à 16,
    sous réserve que
    a) si R1 représente H, n n'est pas inférieur ou égal à 5 ;
    b) si R1 représente CH3, n n'est pas nul ;
    c) et si R1 représente CH3 et si n vaut 1, 3, 4, 5 ou 6, le composé de formule I se présente sous forme d'énantiomère pratiquement pur ;
    ou sel admissible en pharmacie d'un tel composé.
  2. Composé conforme à la revendication 1, dans lequel R1 est différent de R2, sous forme d'énantiomère pratiquement pur de configuration R.
  3. Composé conforme à la revendication 1, dans lequel R1 est différent de R2, sous forme d'énantiomère pratiquement pur de configuration S.
  4. Composé conforme à la revendication 1, ledit composé de formule I étant choisi parmi les suivants :
    (R)-N-(2-butyl)propargylamine,
    (R)-N-(2-pentyl)propargylamine,
    (R)-N-(2-hexyl)propargylamine,
    (R)-N-(2-heptyl)propargylamine,
    (R)-N-(2-octyl)propargylamine,
    (R)-N-(2-nonyl)propargylamine,
    (R)-N-(2-décyl)propargylamine,
    (R)-N-(2-undécyl)propargylamine,
    (R)-N-(2-dodécyl)propargylamine ;
    ou sel admissible en pharmacie d'un tel composé.
  5. Composé conforme à la revendication 1, ledit composé de formule I étant choisi parmi les suivants :
    (S)-N-(2-butyl)propargylamine,
    (S)-N-(2-pentyl)propargylamine,
    (S)-N-(2-hexyl)propargylamine,
    (S)-N-(2-heptyl)propargylamine,
    (S)-N-(2-octyl)propargylamine,
    (S)-N-(2-nonyl)propargylamine,
    (S)-N-(2-décyl)propargylamine,
    (S)-N-(2-undécyl)propargylamine,
    (S)-N-(2-dodécyl)propargylamine ;
    ou sel admissible en pharmacie d'un tel composé.
  6. Composé conforme à la revendication 1, ledit composé de formule I étant choisi parmi les suivants :
    N-(1-octyl)propargylamine,
    N-(1-nonyl)propargylamine,
    N-(1-décyl)propargylamine,
    N-(1-undécyl)propargylamine,
    N-(1-dodécyl)propargylamine ;
    ou sel admissible en pharmacie d'un tel composé.
  7. Composé conforme à l'une des revendications 1 à 6, sous forme de sel chlorhydrate.
  8. Composé conforme à l'une des revendications 1 à 3, dans lequel n représente un nombre entier valant de 1 à 12.
  9. Composé conforme à l'une des revendications 1 à 3, dans lequel n représente un nombre entier valant de 1 à 9.
  10. Composé conforme à la revendication 1, qui est la (R)-N-(2-heptyl)propargylamine.
  11. Emploi d'un composé de formule I :
    Figure 00610001
    dans laquelle
       R1 représente H ou CH3,
       R2 représente CH3(CH2)n,
       et n représente un nombre entier valant de 0 à 16,
    qui est achiral ou qui est un énantiomère R pratiquement pur,
    ou d'un sel admissible en pharmacie d'un tel composé, pour la préparation d'un médicament destiné au traitement ou à la prévention d'un état dans lequel la mort cellulaire intervient par apoptose.
  12. Emploi conforme à la revendication 11, dans lequel l'état est une attaque, un traumatisme crânien, une paralysie de Bell, une lésion par écrasement de la moelle épinière ou d'autres nerfs, la maladie d'Alzheimer, la maladie de Parkinson, la maladie de Pick, la sclérose latérale amyotrophique, la maladie de Huntington, la sclérose en plaque, une myopathie cardiaque, une néphropathie, une rétinopathie, une complication du diabète, un glaucome ou une neuropathie idiopathique.
  13. Emploi conforme à la revendication 11 ou 12, dans lequel le composé de formule I est choisi parmi les suivants :
    N-(éthyl)propargylamine,
    N-(1-propyl)propargylamine,
    N-(2-propyl)propargylamine,
    N-(1-butyl)propargylmine,
    N-(1-pentyl)propargylamine,
    N-(1-hexyl)propargylamine,
    N-(1-heptyl)propargylamine,
    N-(1-octyl)propargylamine,
    N-(1-nonyl)propargylamine,
    N-(1-décyl)propargylamine,
    N-(1-undécyl)propargylamine,
    N-(1-dodécyl)propargylamine,
    (R)-N-(2-butyl)propargylamine,
    (R)-N-(2-pentyl)propargylamine,
    (R)-N-(2-hexyl)propargylamine,
    (R)-N-(2-heptyl)propargylamine,
    (R)-N-(2-octyl)propargylamine,
    (R)-N-(2-nonyl)propargylamine,
    (R)-N-(2-décyl)propargylamine,
    (R)-N-(2-undécyl)propargylamine,
    (R)-N-(2-dodécyl)propargylamine ;
    et leurs sels admissibles en pharmacie.
  14. Emploi conforme à la revendication 11 ou 12, dans lequel le composé de formule I est choisi parmi les suivants :
    N-(1-propyl)propargylamine,
    N-(2-propyl)propargylamine,
    N-(1-butyl)propargylmine,
    N-(1-pentyl)propargylamine,
    N-(1-hexyl)propargylamine,
    N-(1-heptyl)propargylamine,
    N-(1-octyl)propargylamine,
    (R)-N-(2-butyl)propargylamine,
    (R)-N-(2-pentyl)propargylamine,
    (R)-N-(2-hexyl)propargylamine,
    (R)-N-(2-heptyl)propargylamine,
    (R)-N-(2-octyl)propargylamine ;
    et leurs sels admissibles en pharmacie.
  15. Procédé de fabrication d'un médicament destiné au traitement ou à la prévention d'un état dans lequel la mort cellulaire intervient par apoptose, ledit médicament comprenant une quantité active d'un composé de formule I :
    Figure 00630001
    dans laquelle
       R1 représente H ou CH3,
       R2 représente CH3(CH2)n,
       et n représente un nombre entier valant de 0 à 16,
    qui est achiral ou qui est un énantiomère R pratiquement pur,
    ou d'un sel admissible en pharmacie d'un tel composé.
  16. Procédé conforme à la revendication 15, dans lequel l'état est une attaque, un traumatisme crânien, une paralysie de Bell, une lésion par écrasement de la moelle épinière ou d'autres nerfs, la maladie d'Alzheimer, la maladie de Parkinson, la maladie de Pick, la sclérose latérale amyotrophique, la maladie de Huntington, la sclérose en plaque, une myopathie cardiaque, une néphropathie, une rétinopathie, une complication du diabète, un glaucome ou une neuropathie idiopathique.
  17. Procédé conforme à la revendication 15 ou 16, dans lequel le composé de formule I est choisi parmi les suivants :
    N-(éthyl)propargylamine,
    N-(1-propyl)propargylamine,
    N-(2-propyl)propargylamine,
    N-(1-butyl)propargylmine,
    N-(1-pentyl)propargylamine,
    N-(1-hexyl)propargylamine,
    N-(1-heptyl)propargylamine,
    N-(1-octyl)propargylamine,
    N-(1-nonyl)propargylamine,
    N-(1-décyl)propargylamine,
    N-(1-undécyl)propargylamine,
    N-(1-dodécyl)propargylamine,
    (R)-N-(2-butyl)propargylamine,
    (R)-N-(2-pentyl)propargylamine,
    (R)-N-(2-hexyl)propargylamine,
    (R)-N-(2-heptyl)propargylamine,
    (R)-N-(2-octyl)propargylamine,
    (R)-N-(2-nonyl)propargylamine,
    (R)-N-(2-décyl)propargylamine,
    (R)-N-(2-undécyl)propargylamine,
    (R)-N-(2-dodécyl)propargylamine ;
    et leurs sels admissibles en pharmacie.
  18. Procédé conforme à la revendication 15 ou 16, dans lequel le composé de formule I est choisi parmi les suivants :
    N-(1-propyl)propargylamine,
    N-(2-propyl)propargylamine,
    N-(1-butyl)propargylmine,
    N-(1-pentyl)propargylamine,
    N-(1-hexyl)propargylamine,
    N-(1-heptyl)propargylamine,
    N-(1-octyl)propargylamine,
    (R)-N-(2-butyl)propargylamine,
    (R)-N-(2-pentyl)propargylamine,
    (R)-N-(2-hexyl)propargylamine,
    (R)-N-(2-heptyl)propargylamine,
    (R)-N-(2-octyl)propargylamine ;
    et leurs sels admissibles en pharmacie.
  19. Procédé conforme à la revendication 15, dans lequel le composé de formule I se présente sous la forme de sel chlorhydrate.
  20. Composition destinée au traitement ou à la prévention d'un état dans lequel la mort cellulaire intervient par apoptose, laquelle composition comprend une quantité active d'un composé de formule I :
    Figure 00650001
    dans laquelle
       R1 représente H ou CH3,
       R2 représente CH3(CH2)n,
       et n représente un nombre entier valant de 0 à 16,
    qui est achiral ou qui est un énantiomère R pratiquement pur,
    sous réserve que
    a) si R1 représente CH3 et si n vaut de 3 à 6, le composé de formule I soit un énantiomère pur,
    b) et que le composé ne soit pas de la N-(1-hexyl)propargylamine,
    ou d'un sel admissible en pharmacie d'un tel composé, mélangé avec un diluant ou un véhicule admissible en pharmacie.
  21. Composition conforme à la revendication 20, dans laquelle le composé de formule I est choisi parmi les suivants :
    N-(éthyl)propargylamine,
    N-(1-propyl)propargylamine,
    N-(2-propyl)propargylamine,
    N-(1-butyl)propargylmine,
    N-(1-pentyl)propargylamine,
    N-(1-heptyl)propargylamine,
    N-(1-octyl)propargylamine,
    N-(1-nonyl)propargylamine,
    N-(1-décyl)propargylamine,
    N-(1-undécyl)propargylamine,
    N-(1-dodécyl)propargylamine,
    (R)-N-(2-butyl)propargylamine,
    (R)-N-(2-pentyl)propargylamine,
    (R)-N-(2-hexyl)propargylamine,
    (R)-N-(2-heptyl)propargylamine,
    (R)-N-(2-octyl)propargylamine,
    (R)-N-(2-nonyl)propargylamine,
    (R)-N-(2-décyl)propargylamine,
    (R)-N-(2-undécyl)propargylamine,
    (R)-N-(2-dodécyl)propargylamine ;
    et leurs sels admissibles en pharmacie.
  22. Composition conforme à la revendication 20, dans laquelle le composé de formule 1 est choisi parmi les suivants :
    N-(1-propyl)propargylamine,
    N-(2-propyl)propargylamine,
    N-(1-butyl)propargylmine,
    N-(1-pentyl)propargylamine,
    N-(1-heptyl)propargylamine,
    N-(1-octyl)propargylamine,
    (R)-N-(2-butyl)propargylamine,
    (R)-N-(2-pentyl)propargylamine,
    (R)-N-(2-hexyl)propargylamine,
    (R)-N-(2-heptyl)propargylamine,
    (R)-N-(2-octyl)propargylamine,
    et leurs sels admissibles en pharmacie.
  23. Composition conforme à la revendication 20, dans laquelle le composé de formule I se présente sous forme de sel chlorhydrate.
  24. Boíte de médicament commercialisable destinée au traitement ou à la prévention d'un état dans lequel la mort cellulaire intervient par apoptose, laquelle boíte comprend un agent pharmaceutioque de formule I, défini dans la revendication 1, ainsi que des instructions pour l'emploi dans le traitement ou la prévention d'un état dans lequel la mort cellulaire intervient par apoptose.
EP98933408A 1997-07-14 1998-07-14 Propargylamines aliphatiques employes comme antidotes electifs Expired - Lifetime EP0996612B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/891,904 US5840979A (en) 1997-07-14 1997-07-14 Aliphatic propargylamines as cellular rescue agents
US891904 1997-07-14
PCT/CA1998/000683 WO1999003817A2 (fr) 1997-07-14 1998-07-14 Propargylamines aliphatiques employes comme antidotes electifs

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EP0996612B1 true EP0996612B1 (fr) 2003-04-09

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EP0979073A4 (fr) * 1997-03-31 2004-04-07 Childrens Medical Center Nitrosylation effectuee pour inactiver des enzymes apoptotiques
US6809120B1 (en) * 1998-01-13 2004-10-26 University Of Saskatchewan Technologies Inc. Composition containing propargylamine for enhancing cancer therapy
WO2000074726A1 (fr) * 1999-06-07 2000-12-14 The J. David Gladstone Institutes METHODES ET COMPOSITIONS DESTINEES A EMPECHER UNE APOPTOSE A MEDIATION p53
AU2003282337B2 (en) * 2002-11-07 2009-07-16 Technion Research And Development Foundation Ltd. Neuroprotective iron chelators and pharmaceutical compositions comprising them
JP4640923B2 (ja) * 2003-09-05 2011-03-02 株式会社日本触媒 粒子状吸水性樹脂組成物の製造方法
EP1686973A4 (fr) * 2003-11-25 2009-03-25 Technion Res & Dev Foundation Compositions et procedes pour traiter des troubles et des maladies cardiovasculaires
US8097608B2 (en) * 2003-11-25 2012-01-17 Technion Research And Development Foundation Ltd. Methods for treatment of cardiovascular disorders and diseases
JP2005232148A (ja) * 2004-02-03 2005-09-02 Technion Research & Development Foundation Ltd 神経保護剤としてプロパルギルアミンの使用
TWI353360B (en) 2005-04-07 2011-12-01 Nippon Catalytic Chem Ind Production process of polyacrylic acid (salt) wate
US8263655B2 (en) * 2005-10-06 2012-09-11 Technion Research And Development Foundation Ltd Methods for treatment of renal failure
TWI394789B (zh) 2005-12-22 2013-05-01 Nippon Catalytic Chem Ind 吸水性樹脂組成物及其製造方法、吸收性物品
EP1837348B9 (fr) 2006-03-24 2020-01-08 Nippon Shokubai Co.,Ltd. Résine absorbant l'eau et son procédé de fabrication
EP2484439B1 (fr) 2009-09-29 2022-12-14 Nippon Shokubai Co., Ltd. Absorbant particulaire d'eau et son procédé de fabrication
AU2011212068B2 (en) 2010-02-03 2016-08-18 Pharma Two B Ltd. Extended release formulations of rasagiline and uses thereof

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FR1453844A (fr) * 1965-03-19 1966-07-22 Soc Ind Fab Antibiotiques Sifa Nouvelles n-propynyl alcoylamines et leurs sels et procédé de préparation
US5169868A (en) * 1991-03-01 1992-12-08 University Of Saskatchewan Aliphatic propargylamines as specific mao-b inhibitors
CA2066364C (fr) * 1992-04-16 1999-01-26 Romano Salvador Derives de la propargylamine psychoactifs

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JP2001510179A (ja) 2001-07-31
US5840979A (en) 1998-11-24
DE69813228T2 (de) 2004-02-19
WO1999003817A2 (fr) 1999-01-28
EP0996612A2 (fr) 2000-05-03
US6251950B1 (en) 2001-06-26
AU8328998A (en) 1999-02-10
WO1999003817B1 (fr) 1999-07-01
WO1999003817A3 (fr) 1999-05-27
CA2295483A1 (fr) 1999-01-28
DE69813228D1 (de) 2003-05-15

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